Madecassoside exerts anti-neurodegeneration effects in protein l-isoaspartyl methyltransferase deficient mice via targeting PRDX2-mediated oxidative stress and inflammation.

Oxidative stress and neuroinflammation are undoubtedly common etiologies of neurodegenerative diseases, contributing to the disease progression. Madecassoside (MA), a triterpenoid saponin component derived from herbal medicine Centella asiatica, exhibits multiple biological properties including anti-oxidative and anti-inflammatory activities in neurodegenerative disease models. In addition, MA improved the neurodegeneration of protein L-isoaspartyl methyltransferase (PIMT/PCMT1) knockout mice. However, the exact neuroprotective mechanism of action and the targets of MA in PIMT deficient mice remain largely elusive. To address this, the oxidative stress indices including malondialdehyde (MDA), superoxide dismutase (SOD), and peroxiredoxins-2 (PRDX2) levels were detected by using a biochemical method. Pro-inflammatory cytokine (Caspase-1) levels were measured via RT-qPCR. The activation of microglia and astrocyte was examined through immunofluorescence staining of Iba1 (microglia marker) and GFAP (astrocyte marker). The results indicated that PIMT deficiency induced hippocampal oxidative stress and neuroinflammation. Intriguingly, besides the peroxidase activity, the redox-oligoforms of PRDX2 with potential hotspots for the formation L-isoaspartate (L-isoAsp) residue was also affected significantly by PIMT deficiency. In addition, PRDX2 was co-localized with Iba1 and GFAP. Collectively, it was suggested PRDX2 might be involved in aberrant redox homeostasis and microglial neuroinflammation of PIMT deficient mice, which could be improved by MA. Taken together, these findings not only provide novel insight into the underlying mechanism of PIMT deficiency-induced neurodegeneration, but also support the notion that the PIMT-PRDX2 axis is a promising potential therapeutic target for MA as anti-neurodegeneration agent.